ESRD is accompanied by near universal insufficiency of nutritional vitamin D (25-hydroxyvitamin D; 25D). Studies by our group and others suggest 25D is intimately linked to immune defense via alterations in the production of inflammatory cytokines and antimicrobial peptides. These include cathelicidin, which we have shown to identify end-stage renal disease (ESRD) patients at risk for death from infection, the second-leading cause of death in this population. We hypothesize that deficiency of 25D in ESRD leads to an altered immune response, predisposing to early morbidity and mortality from infection. Ergocalciferol, which is rapidly converted to 25D, is the most widely available form of nutritional vitamin D in the US, yet guidelines for its use in ESRD are absent because of limited data supporting its efficacy, safety, and biological effects. To directly address this, we are performing a double-blind, placebo-controlled randomized trial in 105 (new sample size) incident chronic hemodialysis patients (35/arm x 3) with 25D insufficiency (<30ng/ml), comparing two ergocalciferol dosing regimens (50,000 IU/week and 50,000 IU/month) and an identically appearing placebo. The primary outcome will be correction of vitamin D insufficiency at 12 weeks. Serum calcium and phosphate levels will be measured biweekly to assess safety, and blood cytokine and cathelicidin levels will be measured every 4 weeks to assess biological responses. To examine biological effects in greater detail, a subset of subjects from each arm will be further analyzed with serial macrophage gene expression profiles and whole blood cytokine profiles following ex-vivo stimulation with bacterial antigens (e.g., killed S. aureus). As of August 15, 2010, we have randomized 32 subjects into this ARRA supported trial. Furthermore, we have performed ex-vivo studies in 18 of the 30 planned subjects. We have hired additional research assistants and nurses to ensure the success of this study. Our recruitment has averaged ~3.8 subjects per month. We are now seeking 2 years of additional support to expand the enrollment to improve our power (account for dropouts), add an additional clinical site, conclude our ex-vivo and gene expression studies, finalize our analyses, and publish our results. This study, addressing a significant unmet need in nephrology, involves important clinical and translational aims that will advance the care of patients with ESRD. These data will also provide an important foundation for designing clinical trials rigorously assessing the effect of nutritional vitamin D on infectious and other complications in ESRD.